Infantile spasms (IS) are epileptic seizures with distinct pharmacosensitivity that manifest in a spectrum of epileptic encephalopathies of infancy with poor prognosis in terms of subsequent cognitive outcomes and emergence of drug-resistant epilepsy. The current therapies (adrenocorticotropic hormone (ACTH), vigabatrin) are not always effective; their ability to alter long-term outcomes is limited and may be associated with significant side effects. To identify new therapies for IS and comorbidities, we have developed a rat multiple-hit model of IS which demonstrates the chronic evolution of the human IS syndrome: age-specific expression of IS, emergence of other seizures and cognitive deficits. Spasms in this model are refractory to ACTH and transiently responsive to vigabatrin, rendering this a model of refractory IS. We have previously demonstrated the feasibility of preclinical drug testing in our model by showing that carisbamate and rapamycin therapy, given after the onset of spasms, can acutely suppress spasms, and a brief course of rapamycin persistently suppresses spasms with disease modifying effects on learning and memory. Our objective is to validate the role of this model as a preclinical screening tool for the identification of new therapies for medically-refractory SIS with rapid onset, sustained effect, and disease-modifying potential. We propose to use this model to screen the efficacy of several agents (administered after the onset of spasms, as is the case in human babies) and determine: (a) their acute efficacy and duration of effect of a single drug injection on behavioral and electroclinical spasms using time and dose response experiments, and (b) if a pulse administration of selected effective drugs stops spasms, prevents the emergence of other seizures and improves cognition. We will use a randomized, blinded design of time and dose-response experiments to test for acute and sustained efficacy on spasms (primary endpoints) and other seizures and cognitive deficits (secondary experiments). Methods will include stereotactic drug infusions, monitoring for spasms, other seizure types, neurodevelopmental reflexes and cognitive abilities. Drugs that successfully pass this screening algorithm, will be used in subsequent application for funding through a U01 mechanism to complete their preclinical drug development testing, necessary for IND application. If successful, this proposal will validate the role of this model of ACTH-refractory IS as a preclinical screening tool for the identification of new, rapid-onset therapies and test their antiepileptogenic and disease-modifying potential.